A. Field of the Invention
The present invention relates to substituted 1,5-diphenyl-2-pyrrolepropionic acids and derivatives and more particularly relates to the novel compounds of formula I which are specific 5-lipoxygenase inhibitors and are useful as anti-inflammatory and anti-allergy agents.
It is well recognized that arachidonic acid, an essential unsaturated fatty acid, is enzymatically oxygenated to various products, including, prostaglandins, thromboxanes, the 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs) and hydroperoxyeicosatetraenoic acids (HPETEs) and the leukotrienes, all of which have potent physiological effects. The leukotrienes, which are produced via the 5-lipoxygenase pathway, are the major contributors to the onset of the symptoms of asthma, and mediators for immediate hypersensitivity reactions and inflammation.
Leukotrienes are found in inflammatory exudates and are involved in the process of cellular invasion during inflammation. The term "leukotrienes" is used as a generic term to describe a class of substances, such as slow-reacting substance (SRS) which is an important mediator in asthma and other immediate hypersensitivity reactions. Immunologically generated SRS is usually referred to as slow-reacting substance of anaphylaxis (SRS-A). SRS-A consists of leukotrienes (LT) known as A.sub.4, B.sub.4, C.sub.4, D.sub.4, and E.sub.4. LTC.sub.4 is at least 100 times more potent than histamine in causing long lasting bronchoconstricting effects. The leukotrienes also increase vascular permeability and cause decreased cardiac output and impaired ventricular contraction. LTB.sub.4 may be an important mediator of inflammation in inflammatory bowel disease.
Chemotaxis is a reaction by which the direction of migration of cells is determined by substances in their environment. It is one of the major processes bringing leukocytes from the blood to an inflammatory site, whether the inflammation is caused by an infectious agent, allergic challenge, or other pro-inflammatory stimuli. LTB.sub.4 is not only cheomtactic for neutrophils and monocytes, but is also highly active in stimulating eosinophil locomotion. LTB.sub.4 also stimulates calcium influx and aggregation of polymorphonuclear leukocytes and LTB.sub.4 may, thus, play an important role in mediating both acute and chronic inflammation.
Rheumatiod spondylitis is characterized by an acute neutrophil flare in the joint which is associated with elevated levels of LTB.sub.4. LTB.sub.4 is also present in gouty effusions; and exposure to urate crystals is known to stimulate LTB.sub.4 production by neutrophils. Accordingly, the 5-lipoxygenase inhibitors of the present invention through inhibition of neutrophil attraction and activation in arthritic joints should reduce the protease and oxidative burden believed responsible for joint destruction in arthritic diseases.
Aspirin and the other non-steroidal anti-inflammatory agents (NSAIDs) such as indomethacin, ibuprofen, fenoprofen, and the like, inhibit the synthesis of prostaglandins via the cyclooxygenase pathway of arachidonic acid metabolism. These prostaglandin synthetase inhibitors generally exhibit anti-inflammatory, anti-pyretic and analgesic activity, and are widely used in the treatment of arthritis. The non-steroidal anti-inflammatory agents can lead to the formation of additional pro-inflammatory derivatives of arachidonic acid produced through the 5-lipoxygenase pathway which play a role in immediate hypersensitivity reactions and also have pronounced inflammatory effects. Administration of the NSAIDs alone can produce allergic reactions including bronchospastic reactivity; skin rashes; syndrome of abdominal pain, fever, chills, nausea and vomiting; and anaphylaxis. For this reason, aspirin and the other non-steroidal anti-inflammatory agents (NSAIDs) are generally contraindicated for patients suffering from asthma or who have previously exhibited allergic sensitivity to aspirin or other NSAIDs. Co-administration of the 5-lipoxygenase inhibitors of this invention with cyclooxygenase inhibitors may mitigate the untoward side effects of the latter and allow the increased advantageous use of such cyclooxygenase inhibitors.
Prior to the recognition of the significance of the 5-lipoxygenase pathway of arachidonic acid metabolism in allergic reactions and inflammation, the search for effective therapeutic agents was based primarily on those agents which treated the symptoms of allergy and inflammation. There has since been effort to develop new drugs which selectively block the formation of the mediators of these conditions, and the present invention provides substituted 1,5-diphenyl-2-pyrrolepropionic acid and derivatives which are inhibitors of the 5-lipoxygenase pathway and are useful in the treatment of asthma, rheumatoid arthritis, psoriasis, and other allergy, hypersensitivity reactions, and inflammatory conditions.
See Bengt Sameusson, "Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and Inflammation", Science, Vol. 220, pp. 568-575 (May 1983); Michael K. Bach, "Inhibitors of Leukotriene Synthesis and Action", The Leukotrienes, Chemistry and Biology, pp 163-194 (Academic Press, Inc., 1984); C. W. Lee et al., "Human Biology and Immunoreactivity of Leukotrienes", Advances in Inflammation Research, Volume 6, pp 219-225 (Raven Press, New York 1984); Editorial, "Leukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and Dermatoses", Arch. Dermatol, Vol. 119, pp 541-547 (July, 1983); Robert A. Lewis et al., "A Review of Recent Contributions on Biologically active Products of Arachidonate Conversion", Int. J. Immunopharmac., Vol. 4, No. 2, pp 85-90 (1982); Michael K. Bach, Biochemical Pharmacology, Vol. 23, No. 4, pp 515-521 (1984); and E. L. Becker, Chemotactic Factors of Inflammation, pp 223-225 (Elsevier Science Publishers V.B., Amsterdam, 1983); Sharon, P. and Stenson, W. F., Gastroenterology, Vol. 84, 454 (1984); and Musch, M. W. et al., Science, Vol. 217, 1255 (1982).
The present invention provides compounds which block the 5-lipoxygenase metabolic pathway and, therefore, block the formation of the leukotrienes resonsible for allergy and inflammation, and represent a new class of therapeutic agents which are useful in the treatment of allergic and hypersensitivity reactions and inflammation, alone, or also may be utilized in combination with cyclooxygenase inhibitors such as the non-steroidal anti-inflammatory agents.
B. Prior Art
Chinn, U.S. Pat. No. 3471513, discloses 2-(2-carboxyethyl)-5-phenyl-1-pyrrole-butyric acid and congeners and the antibiotic and ulcer-inhibiting properties of same.
Chinn, U.S. Pat. No. 3475451 discloses 5-substituted phenyl-2-pyrrolepropionamides and derivatives of the formula ##STR2## as having analgesic, anti-bacterial and anti-algal properties.
U.S. Pat. No. 3542788, Chinn et al., discloses compounds of the formula ##STR3## in which AM represents an amino radical, M represents hydrogen or alkyl, and Ph represents phenyl optionally substituted by halogen and/or alkoxy. The foregoing compounds are disclosed as having anti-protozoal, anti-bacterial, anti-inflammatory, and anti-ulcerogenic properties.
U.S. Pat. No. 3168529 discloses anti-inflammatory 1-(p-lower alkanoylphenyl)-5-arylpyrrole-2-propionic acids of the formula: ##STR4## in which Z represents hydrogen, halogen, lower-alkyl, alkoxy or alkylthiol.
In contrast to the above described prior art compounds, the compounds of the present invention contain a substituted phenol directly attached to the pyrrole nitrogen in which the hydroxy group thereof (or precursor) is ortho to the nitrogen atom, i.e. ##STR5## which configuration has now been found to be essential to obtaining the desired 5-lipoxygenase inhibitory activity in these pyrrole derivatives. Moreover, the resultant 5-lipoxygenase inhibitory properties of the present compounds and their ultimate utility in the treatment of inflammation and allergic or hypersensitivity conditions, e.g. asthma, are not disclosed in the foregoing prior art.